PROJECT SUMMARY/ABSTRACT The goal of this project is to further develop a novel MR molecular imaging technique for mapping glucose uptake and to apply this technique for stroke imaging. Glucose uptake is critical for cellular function, and the ability to assess its alteration in diseases holds great promise in many fields of medicine including neurodegeneration, traumatic brain injury, tumors, and specifically for this application, stroke. In acute ischemic stroke, a major therapeutic goal is to rescue the penumbra, i.e., tissue at risk of infarction but can be rescued with timely intervention. Robust identification of penumbra is crucial because it would potentially expand the therapeutic window, a major limiting factor in access to acute stroke intervention, and help with patient selection for novel endovascular therapies and the development of neuroprotective treatments. However, accurate and prompt imaging of penumbra is still a clinical barrier. We have recently developed a chemical-exchange sensitive spin- lock (CESL) MRI technique to indirectly detect glucose via the rapid chemical exchange between glucose hydroxyl groups and water protons. In contrast to direct measurements of glucose, such indirect detection through water offers substantial sensitivity enhancement, making in vivo mapping of glucose uptake feasible. Our preliminary results show that in stroke animals, CESL MRI with injection of a glucose analog can quickly (within several minutes) identify an apparent elevation of glucose uptake in a region adjacent to the ischemic core. This region of elevated response correlates well with final tissue outcome. While administration of natural D-glucose leads to hyperglycemia and worsens the ischemic tissue outcome, xylose, an FDA-approved glucose analog, may help alleviate the harmful metabolic effects and potentially improve the tissue outcome. In Aim 1, we will further develop xylose-CESL to increase its signal sensitivity for glucose uptake imaging. In Aim 2, we will study the signal source, sensitivity, and spatiotemporal characteristics of the xylose-CESL signal in ischemic rat brain. In Aim 3, we will evaluate the efficacy of xylose-CESL for penumbra imaging. Successful completion of this project will provide a powerful MR molecular imaging tool for acute ischemic stroke, which would immediately impact preclinical studies and have a great potential for clinical translation.